TY - JOUR
T1 - Clinical implications of monitoring nivolumab immunokinetics in non-small cell lung cancer patients
AU - Osa, Akio
AU - Uenami, Takeshi
AU - Koyama, Shohei
AU - Fujimoto, Kosuke
AU - Okuzaki, Daisuke
AU - Takimoto, Takayuki
AU - Hirata, Haruhiko
AU - Yano, Yukihiro
AU - Yokota, Soichiro
AU - Kinehara, Yuhei
AU - Naito, Yujiro
AU - Otsuka, Tomoyuki
AU - Kanazu, Masaki
AU - Kuroyama, Muneyoshi
AU - Hamaguchi, Masanari
AU - Koba, Taro
AU - Futami, Yu
AU - Ishijima, Mikako
AU - Suga, Yasuhiko
AU - Akazawa, Yuki
AU - Machiyama, Hirotomo
AU - Iwahori, Kota
AU - Takamatsu, Hyota
AU - Nagatomo, Izumi
AU - Takeda, Yoshito
AU - Kida, Hiroshi
AU - Akbay, Esra A.
AU - Hammerman, Peter S.
AU - Wong, Kwok Kin
AU - Dranoff, Glenn
AU - Mori, Masahide
AU - Kijima, Takashi
AU - Kumanogoh, Atsushi
PY - 2018/10/4
Y1 - 2018/10/4
N2 - BACKGROUND: The PD-1-blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events. METHODS: To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non-small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up. RESULTS: Prolonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2-15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response. CONCLUSIONS: Although only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, UMIN000024623. FUNDING: This work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).
AB - BACKGROUND: The PD-1-blocking antibody nivolumab persists in patients several weeks after the last infusion. However, no study has systematically evaluated the maximum duration that the antibody persists on T cells or the association between this duration and residual therapeutic efficacy or potential adverse events. METHODS: To define the duration of binding and residual efficacy of nivolumab after discontinuation, we developed a simplified strategy for T cell monitoring and used it to analyze T cells from peripheral blood from 11 non-small cell lung cancer patients previously treated with nivolumab. To determine the suitability of our method for other applications, we compared transcriptome profiles between nivolumab-bound and nivolumab-unbound CD8 T cells. We also applied T cell monitoring in 2 nivolumab-treated patients who developed progressive lung tumors during long-term follow-up. RESULTS: Prolonged nivolumab binding was detected more than 20 weeks after the last infusion, regardless of the total number of nivolumab infusions (2-15 doses) or type of subsequent treatment, in 9 of the 11 cases in which long-term monitoring was possible. Ki-67 positivity, a proliferation marker, in T cells decreased in patients with progressive disease. Transcriptome profiling identified the signals regulating activation of nivolumab-bound T cells, which may contribute to nivolumab resistance. In 2 patients who restarted nivolumab, T cell proliferation markers exhibited the opposite trend and correlated with clinical response. CONCLUSIONS: Although only a few samples were analyzed, our strategy of monitoring both nivolumab binding and Ki-67 in T cells might help determine residual efficacy under various types of concurrent or subsequent treatment. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, UMIN000024623. FUNDING: This work was supported by Japan Society for the Promotion of Science KAKENHI (JP17K16045, JP18H05282, and JP15K09220), Japan Agency for Medical Research and Development (JP17cm0106310, JP18cm0106335 and JP18cm059042), and Core Research for Evolutional Science and Technology (JPMJCR16G2).
KW - Cancer immunotherapy
KW - Immunology
KW - Lung cancer
KW - Pulmonology
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U2 - 10.1172/jci.insight.59125
DO - 10.1172/jci.insight.59125
M3 - Article
C2 - 30282824
AN - SCOPUS:85063243616
SN - 2379-3708
VL - 3
JO - JCI Insight
JF - JCI Insight
IS - 19
ER -